Jefferies first achieved international attention after he was attacked onstage while performing at the Manchester Comedy Store. At one time, Jefferies incorporated the incident, including its video recording, into his act: this can be seen on his 2008 DVD Contraband. He became well known in the US after his debut standup special on HBO.
Jefferies has performed at numerous festivals, including the Edinburgh Fringe, Just for Laughs Festival, South African Comedy Festival Cape Town, Reading and Leeds Festivals and the Glastonbury Festival. He has appeared on British comedy panel shows such as Never Mind the Buzzcocks, Have I Got News for You, The Heaven and Earth Show and 8 Out of 10 Cats and the US comedy panel show The Green Room with Paul Provenza. Jefferies has also performed spots on The World Stands Up, Comedy Blue and Edinburgh and Beyond for Comedy Central.